Pharmacogenomics of Taxane/Platinum Therapy in Ovarian Cancer

Abstract The advent of high-throughput technologies has generated diverse omic data including single-nucleotide polymorphisms, copy-number variation, gene expression, methylation, and metabolites. The next major challenge is how to integrate those multi-omic data for downstream analyses to enhance our biological insights. This emerging approach is known as multi-omic data integration, which is in contrast to studying each omic data type independently. I will discuss challenging issues in developing algorithms and methods for multi-omic data integration. The particular focus will be given to the potential for combining diverse types of FAANG data and the utility of multi-omic data integration in association analysis and phenotypic prediction.

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The Interplay between Long Noncoding RNAs and Proteins of the Epigenetic Machinery in Ovarian Cancer

Cancers ◽

10.3390/cancers12092701 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2701

Author(s):

Naiade Calanca ◽

Cecilie Abildgaard ◽

Cláudia Aparecida Rainho ◽

Silvia Regina Rogatto

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Noncoding Rnas ◽

Response To Therapy ◽

Long Noncoding Rnas ◽

Cancer Type ◽

Aberrant Expression ◽

Term Survival ◽

Control Of Gene Expression ◽

Epigenetic Machinery

Comprehensive large-scale sequencing and bioinformatics analyses have uncovered a myriad of cancer-associated long noncoding RNAs (lncRNAs). Aberrant expression of lncRNAs is associated with epigenetic reprogramming during tumor development and progression, mainly due to their ability to interact with DNA, RNA, or proteins to regulate gene expression. LncRNAs participate in the control of gene expression patterns during development and cell differentiation and can be cell and cancer type specific. In this review, we described the potential of lncRNAs for clinical applications in ovarian cancer (OC). OC is a complex and heterogeneous disease characterized by relapse, chemoresistance, and high mortality rates. Despite advances in diagnosis and treatment, no significant improvements in long-term survival were observed in OC patients. A set of lncRNAs was associated with survival and response to therapy in this malignancy. We manually curated databases and used bioinformatics tools to identify lncRNAs implicated in the epigenetic regulation, along with examples of direct interactions between the lncRNAs and proteins of the epigenetic machinery in OC. The resources and mechanisms presented herein can improve the understanding of OC biology and provide the basis for further investigations regarding the selection of novel biomarkers and therapeutic targets.

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Genetics of Schizophrenia and Bipolar Disorder

10.1093/med/9780190681425.003.0013 ◽

2017 ◽

Author(s):

Alexander Charney ◽

Pamela Sklar

Keyword(s):

Bipolar Disorder ◽

Copy Number ◽

Psychotic Disorders ◽

Copy Number Variants ◽

Nucleotide Polymorphisms ◽

Common Variants ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. There is now convincing genetic evidence that indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, and there is evidence for polygenicity. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder.

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Thymidylate synthase (TS) expression as a prognostic molecular marker in stage II/III colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3577 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3577-3577

Author(s):

Dirk Klingbiel ◽

Edoardo Missiaglia ◽

Pu Yan ◽

Sabine Tejpar ◽

Arnaud Roth ◽

...

Keyword(s):

Gene Expression ◽

Thymidylate Synthase ◽

Copy Number ◽

Cox Regression ◽

Gene Copy Number ◽

Tumor Grade ◽

Gene Copy ◽

Allelic Loss ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

3577 Background: Studies on the association between colorectal cancer (CC) outcome and thymidylate synthase expression have provided inconsistent results. In this study we attempted to resolve the issue by assessing the associations between TS expression and outcome in a population of primary CC patients (pts), who after resection were randomized to 5-FU/FA vs. FOLFIRI adjuvant therapy. Methods: Immunohistochemical staining for TS protein was successfully performed for 1211 pts in the PETACC3 trial. TS immunoreactivity was scored as high expression (≥75% positive) and low expression (<75% positive). Gene expression respectively copy number data were available for 853 respectively 306 of these samples. Twelve single nucleotide polymorphisms (SNPs) close to the TYMS gene were assessed in 923 pts. Association of variables with relapse-free (RFS) and overall survival (OS) was assessed using Cox regression models. Results: High TS expression and RNA level were strongly associated (log fold change 0.65, p<0.001). Both were significantly higher in proximal CC. As expected, both were associated with other characteristics of proximal CC: MSI, BRAF mutation, high tumor grade. RNA was significantly correlated with gene copy number, distal CC showing more frequent allelic loss. Three SNPs were associated with gene expression which was validated in data from the 1000 genomes project, but none with survival. High TS expression was more strongly associated with better OS in pts receiving FOLFIRI (HR 0.4, 95% CI 0.3–0.6, p<0.001), than 5-FU/FA (HR 0.8, 95% CI 0.5–1.1, p=0.13), with a significant interaction (p=0.05). Similar results were observed for RFS (HR 0.5, p<0.001 vs. HR 0.7, p=0.07; interaction p=0.11). TS expression is still highly prognostic in multivariate models adjusting for factors associated with risk or proximal tumors in FOLFIRI treated pts (OS: HR 0.5, p=0.008; RFS: HR 0.6, p=0.02), but not in F-FU/FA treated pts (OS and RFS: HR=1, p=1). Conclusions: TS expression is lower in distal CC, partly due to deletion of the TYMS locus. Pts with high TS expression have longer RFS and OS, notably when treated with FOLFIRI. For these pts addition of irinotecan to 5-FU/FA adjuvant chemotherapy might be considered. Clinical trial information: NCT00026273.

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Quantitative Analysis of Single Nucleotide Polymorphisms within Copy Number Variation

PLoS ONE ◽

10.1371/journal.pone.0003906 ◽

2008 ◽

Vol 3 (12) ◽

pp. e3906 ◽

Cited By ~ 19

Author(s):

Soohyun Lee ◽

Simon Kasif ◽

Zhiping Weng ◽

Charles R. Cantor

Keyword(s):

Quantitative Analysis ◽

Single Nucleotide Polymorphisms ◽

Copy Number Variation ◽

Copy Number ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Number Variation

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Detection of copy number variation and single nucleotide polymorphisms in genes involved in drug resistance and other phenotypic traits in P. falciparum clinical isolates collected from Uganda

Acta Tropica ◽

10.1016/j.actatropica.2012.11.013 ◽

2013 ◽

Vol 125 (3) ◽

pp. 269-275 ◽

Cited By ~ 5

Author(s):

Mpungu Steven Kiwuwa ◽

Justus Byarugaba ◽

Mats Wahlgren ◽

Fred Kironde

Keyword(s):

Drug Resistance ◽

Single Nucleotide Polymorphisms ◽

Copy Number Variation ◽

Copy Number ◽

Clinical Isolates ◽

Phenotypic Traits ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Number Variation

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Genetics of Schizophrenia and Bipolar Disorder

Neurobiology of Mental Illness ◽

10.1093/med/9780199934959.003.0018 ◽

2013 ◽

pp. 232-246 ◽

Cited By ~ 1

Author(s):

Pamela Sklar

Keyword(s):

Bipolar Disorder ◽

Copy Number ◽

Psychotic Disorders ◽

De Novo ◽

Copy Number Variants ◽

Nucleotide Polymorphisms ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Sequencing Studies ◽

Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. The explosion of strong and convincing genetic evidence indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. There is a role for rare single nucleotide variation as well as de novo genetic variation being pointed to in new sequencing studies, but their overall contribution to risk is less clear. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, there is evidence for polygenicity and as yet no deep sequencing surveys have been published. Several intriguing biological pathways are suggested by these genetic findings related to microRNAs and calcium channel signaling. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder. Translating these results into biological and etiological understanding has not yet advanced, and will likely only do so when experimental methods are developed than can address the large numbers of genes and variants within them that, along with environmental and stochastic effects, result in the development of disease for a particular person.

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X-linked inhibitor of apoptosis single nucleotide polymorphisms and copy number variation are not risk factors for asthma

Respirology ◽

10.1111/resp.12065 ◽

2013 ◽

Vol 18 (4) ◽

pp. 697-703 ◽

Cited By ~ 2

Author(s):

Eugene Roscioli ◽

Rhys Hamon ◽

Richard E. Ruffin ◽

Peter Zalewski ◽

Janet Grant ◽

...

Keyword(s):

Risk Factors ◽

Single Nucleotide Polymorphisms ◽

Copy Number Variation ◽

Copy Number ◽

Inhibitor Of Apoptosis ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Number Variation

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Genome-Wide Genotype-Expression Relationships Reveal Both Copy Number and Single Nucleotide Differentiation Contribute to Differential Gene Expression between Stickleback Ecotypes

Genome Biology and Evolution ◽

10.1093/gbe/evz148 ◽

2019 ◽

Vol 11 (8) ◽

pp. 2344-2359 ◽

Cited By ~ 2

Author(s):

Yun Huang ◽

Philine G D Feulner ◽

Christophe Eizaguirre ◽

Tobias L Lenz ◽

Erich Bornberg-Bauer ◽

...

Keyword(s):

Gene Expression ◽

Copy Number ◽

Gasterosteus Aculeatus ◽

Gene Copy ◽

Nucleotide Polymorphisms ◽

Significant Positive Association ◽

Single Nucleotide ◽

Regulatory Regions ◽

Genome Wide ◽

Habitat Differences

Abstract Repeated and independent emergence of trait divergence that matches habitat differences is a sign of parallel evolution by natural selection. Yet, the molecular underpinnings that are targeted by adaptive evolution often remain elusive. We investigate this question by combining genome-wide analyses of copy number variants (CNVs), single nucleotide polymorphisms (SNPs), and gene expression across four pairs of lake and river populations of the three-spined stickleback (Gasterosteus aculeatus). We tested whether CNVs that span entire genes and SNPs occurring in putative cis-regulatory regions contribute to gene expression differences between sticklebacks from lake and river origins. We found 135 gene CNVs that showed a significant positive association between gene copy number and gene expression, suggesting that CNVs result in dosage effects that can fuel phenotypic variation and serve as substrates for habitat-specific selection. Copy number differentiation between lake and river sticklebacks also contributed to expression differences of two immune-related genes in immune tissues, cathepsin A and GIMAP7. In addition, we identified SNPs in cis-regulatory regions (eSNPs) associated with the expression of 1,865 genes, including one eSNP upstream of a carboxypeptidase gene where both the SNP alleles differentiated and the gene was differentially expressed between lake and river populations. Our study highlights two types of mutations as important sources of genetic variation involved in the evolution of gene expression and in potentially facilitating repeated adaptation to novel environments.

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